Activation of the Bile Acid Receptor FXR Reduces Fibrosis in Mouse Kidney Slices, Whereas TGR5 Agonism Induces Nephrotoxicity

Background: Fibrosis is a key driver of chronic kidney disease (CKD) progression. Yet, unfortunately, there are currently no effective therapies for renal fibrosis. Recent cell- and animal studies suggest that activation of the Farnesoid X Receptor (FXR) and Takeda G Protein-Coupled Receptor 5 (TGR5), two canonical bile acid receptors (BARs), can attenuate fibrosis, making them a promising therapeutic target. Objective: This study investigated the impact of FXR and TGR5 agonism in mouse precision-cut kidney slice (mPCKS) in order to elucidate the mechanism of action directly in kidney tissue. Hypothesis: We hypothesize that activation of FXR and TGR5 will attenuate fibrosis development in mPCKS. Methods: Kidneys were collected from C57BL/6 mice, and mPCKS were subsequently prepared using an Alabama RD Tissue Slicer. mPCKS were cultured for up to 48 hours, either treated with 100 µM chenodeoxycholic acid (CDCA; a FXR agonist), 100 µM lithocholic acid (LCA; a TGR5 agonist), 10ng/mL TGF-β, 10ng/mL TGF-β in combination with 100 µM CDCA, or left untreated. Afterwards, fibrosis was assessed via qPCR for fibrotic markers fibronectin ( Fn ) and collagen 1A1 ( Col1a1 ) and Western blot for FN. In addition, viability and cell death were assessed by ATP levels, TUNEL staining, and caspase-3 (CASP3) Western blot. Results: Treatment with CDCA markedly reduced the gene levels of Col1a1 and protein levels of FN in mPCKS, without affecting viability of the tissue. Its antifibrotic effects were further validated in mPCKS exposed to the profibrotic cytokine TGF-β, resulting in a similar reduction in Col1a1 gene levels and FN protein levels. In contrast, LCA exposure significantly reduced ATP levels, suggesting decreased tissue viability. This was accompanied by increased apoptosis, as evidenced by enhanced TUNEL staining and reduced CASP3 protein levels. Discussion and Conclusion: This study demonstrates that FXR activation with CDCA reduces fibrosis in mPCKS. Surprisingly, LCA, which has been shown to be antifibrotic in animal models, induced apoptosis in mPCKS. Thus, LCA might not be a suitable drug candidate and further studies in human translational models are needed to elucidate the antifibrotic potential of TGR5 agonism. This study was funded by the Lundbeck Foundation. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.